{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐221 is frequently overexpressed in a wide range of human malignancies and functions largely as an oncomiR by targeting key cell cycle inhibitors and receptor tyrosine kinases. In papillary thyroid carcinoma, elevated miR‐221 levels are associated with early carcinogenesis and downregulation of KIT, while in breast cancer its up‐regulation contributes to tamoxifen resistance by suppressing the cyclin‐dependent kinase inhibitor p27(Kip1). Similar mechanisms are observed in hepatocellular carcinoma, where miR‐221 enhances cell proliferation by targeting p27 as well as other regulators (e.g., p57), and in aggressive prostate and thyroid carcinomas where suppression of p27 promotes cell cycle progression and clonogenicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in cell cycle control, miR‐221 modulates several oncogenic signaling pathways and influences the response to therapy. In glioblastoma and other tumors, miR‐221 promotes cell survival and invasion by inhibiting p27 and related targets, with additional evidence from studies showing its involvement in modulating NF‐κB activity via alterations in 3′UTR structure. In estrogen receptor–positive breast cancers, both endogenous and exosome‐mediated transfer of miR‐221 confers resistance to antiestrogen agents such as tamoxifen and fulvestrant. MiR‐221 is also induced in vascular smooth muscle cells by PDGF stimulation, thereby regulating differentiation and proliferation. Furthermore, studies in prostate cancer and chronic lymphocytic leukemia indicate that miR‐221 can drive androgen independence and deregulate cell cycle progression through its negative regulation of p27. Its role in promoting epithelial-to-mesenchymal transition (EMT) in basal-like breast cancer and its emergence as a circulating biomarker in colorectal cancer further highlight its multifaceted contributions to tumor aggressiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, the expression and impact of miR‐221 can be context dependent. In some studies—particularly in high‐risk or advanced cases of prostate cancer and in certain glioma models—lower miR‐221 levels correlate with more aggressive disease and distinct alterations in downstream signaling (including JAK/STAT, mTOR, and TGF‐β pathways), suggesting that in these settings miR‐221 may serve as a nuanced biomarker. Such dichotomy underscores the complexity of miR‐221’s regulatory network and its potential utility both as a prognostic indicator and as a therapeutic target across different tumor types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Huiling He, Krystian Jazdzewski, Wei Li, et al. 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